Myelodysplastic syndrome (MDS) is a group of disorders characterized by dysfunctional blood cells that can progress to acute myeloid leukemia (AML). At this time the etiology of MDS development and progression to AML is not understood and there is no cure (median survival at time of diagnosis is less than 5 years). Yet, DNA damage and mutations appear to play a key role with the initiating defect in a hematopoietic stem cell (HSC). In support, people with certain DNA repair defective syndromes including Fanconi anemia (FA) and Bloom syndrome (BS) exhibit MDS. Interestingly, FA and BS are mechanistically related since the BS protein associates with proteins in the FA pathway and since both influence the repair of DNA double-strand breaks (DSBs) through the homologous recombination (HR) pathway. In addition, some DNA damaging agents appear to predispose people to MDS/AML including ?-radiation and benzene. Both of these agents cause chromosomal abnormalities and HR repairs ?-radiation-induced DSBs. Furthermore, another DSB repair pathway, nonhomologous end joining (NHEJ) may enable the progression of MDS/AML by facilitating chromosomal translocations. Thus, DNA damage and DNA repair appear to be integral factors in the etiology of MDS/AML. This proposal is a collaboration between two labs with expertise in MDS/AML, (Dr. Rebel's lab) and DNA damage/repair (Dr. Hasty's lab). Dr. Rebel has studied MDS/AML in a Crebbp-deficient mouse model. Crebbp is a transcriptional coactivator and Crebbp-deficient mice invariably develop MDS with age that often progress to AML. Importantly, these mice are defective for repairing ?-radiation-induced DNA breaks and exhibit elevated mutation levels in fetal liver cells. Thus, Dr. Rebel's analysis on Crebbp-deficient mice support observations made on patients that DNA damage and defects in DNA repair are causal factors in MDS/AML. Therefore, the hypothesis is that fully functional HR is critical for suppressing MDS/AML in response to genotoxins that cause DSBs while NHEJ generates chromosomal translocations that cause MDS/AML. Two specific aims are presented to address the hypothesis. Crebbp-deficient mouse embryonic stem (ES) cells (Specific Aim 1) and mice (aim 2) will be investigated for the dynamics of repairing ?-radiation- and benzene-induced DNA lesions and the development of MDS and progression to AML. It is anticipated that this will lead to a better understanding of the role that DNA damage/repair plays in disease progression, the impact these genotoxins have on a variety of bone marrow cells including HSCs and vulnerable times of exposure (embryonic development vs. adult). Thus, results from this proposal will elucidate the pathobiology of MDS/AML.